Diagnostic criteria for Stickler syndrome based on comprehensive clinical and molecular analysis

Stickler syndrome is a heterogeneous disorder variably affecting the ocular, orofacial, auditory and skeletal system. Mutations in COL2A1, COL11A1 and COL11A2 have been found to cause Stickler syndrome and result in slightly distinct phenotypes, referred to as type 1, type 2 and type 3 respectively. Due to the large phenotypic variability, no consensus about minimal clinical diagnostic criteria exists. Currently, diagnosis is mainly based on expert opinion and positive mutation analysis. The aim of this study is to better define the syndrome and its different types by creating clinically-based guidelines. Medical records of more than 250 probands with a clinical suspicion of Stickler syndrome were reviewed for relevant symptoms and molecular results. COL2A1 analysis was performed in all patients, and COL11A1 and COL11A2 were subsequently analyzed in the COL2A1-negative patients. In 90% of the probands, the disease-causing mutation was detected, of which 82% was located in the COL2A1 gene, 14% in COL11A1 and 4% in COL11A2. Most COL2A1 mutations lead to haploinsufficiency (nonsense mutations, out-of-frame deletions), whereas the majority of mutations in COL11A1/COL11A2 exhibit a dominant-negative effect (in-frame exon deletions, glycine substitutions). Symptoms that are more present in the mutation-positive patients and thus stronger direct towards Stickler syndrome, are high myopia, retinal detachment, cleft palate and a positive familial history suggesting autosomal dominant inheritance. Hearing loss, joint hypermobility and premature arthropathy are frequently found in Stickler syndrome, but are less specific. The main characteristics differentiating the three types of Stickler syndrome are appearance of the vitreous (membranous in type 1, beaded in type 2 and normal in type 3) and severity of hearing loss (mild high-frequency hearing loss in type 1, moderate pan-frequency hearing loss in type 2 and type 3), although this distinction is not absolute. Based on these clinical as well as molecular results, diagnostic criteria for the different types of Stickler syndrome using a point-scale of different symptoms are proposed. These novel criteria may guide clinicians to better diagnose Stickler syndrome and might help to select the correct molecular analysis